# Neutrophil derived proteinases abolish the IFNG signature in NSCLC

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $555,585

## Abstract

ABSTRACT
Although immune checkpoint inhibitor (ICI) therapy has been a tremendous clinical success, just ~20% of non-
small cell lung cancer (NSCLC) patients respond to anti-PD1/PDL1 therapy. The two major factors predictive of
favorable treatment response to ICI therapy are the presence of the IFNG signature and evidence of CD8+ T cell
infiltration into malignant tumor. Work from our group has shown that neutrophil infiltrated non-small cell lung
cancers do not display the IFNG signature, do not display CD8+ infiltration into malignant tumor, and do not
respond to ICI treatment. Our hypothesis to explain these observations is that tumor-associated neutrophils
release proteinases that degrade key cytokines (IFNG), chemokines (CXCL-9, -10, -11) and a chemokine
receptor (CXCR3) that destroys the IFNG mediated chemotactic gradient that facilitates T cell infiltration into
tumors. The proposed studies will demonstrate that a number of key neutrophil-derived proteinases are capable
of degrading T cell recruiting chemokines and CXCR3 and identify the novel cleavage products resulting from
these events. The functional consequences of these proteolytic events will be demonstrated in novel multicellular
tumor-in-chip systems and in state-of-the art mouse models of lung cancer. Lastly, we will employ a combined
fluorescent in-situ hybridization (FISH) and multiplexed immunohistochemistry (M-IHC) panel to study the
relationship between CXCL9 expressing tumor cells, infiltrating CD8+CXCR3+ T cells, and TAN and determine
the impact that these measures have on ICI treatment outcomes in NSCLC patients.

## Key facts

- **NIH application ID:** 10884281
- **Project number:** 5R01CA282465-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** A McGarry Houghton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $555,585
- **Award type:** 5
- **Project period:** 2023-07-07 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884281

## Citation

> US National Institutes of Health, RePORTER application 10884281, Neutrophil derived proteinases abolish the IFNG signature in NSCLC (5R01CA282465-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10884281. Licensed CC0.

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